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Osteogenesis Imperfecta Nadia Smati Genomics and Medicine The Brittle Bone Disease “Imperfect Bone Formation” Congenital Caused by various gene mutations that affect Collagen -Type 1 Collagen Critical Bone Structure -Severity of defect impacts severity of OI 8 Different types- various characteristics/mutations/consequences Affects 6-7/100,000 People World Wide (I and IV most common) 4 Genes COL1A1,COL1A2, CTRAP, AND LEPRE1 COL1A1/COL1A2 -Cause more than 90% of OI cases -Types I,II,III,and IV -Similar function- produce Type I collagen -Different Chromosome Locations/Severity -Type I- Premature termination of codons -Type II,III,IV-Amino Acid Substitution of Glycine -Functional Consequence: Deficiency of Collagen/Fail to Produce Enough CTRAP/LEPRE1 -Rare, severe cases (although II is the most severe type) -Functional Consequence: Disrupt production of Collagen Molecules themselves -CTRAP-TypeVI /LEPRE1-Type VIII *NOT all genes known- still cases found without an identified mutation in any of the 4 genes Inheritance Variance Most common: Autosomal Dominant Some cases (type VII) found to be Autosmal Recessive 35% Cases found to be De Nova Mutation Full Penetrance for Autosmal Dominant Types of OI Key Distinguishing FactorsCollagen Quality and Quantity based on mutation Genetic Differences/Mutations used to Classify Types (COL1A1/COL1A2) I-Sufficient Quality/Insufficient Quantity (*Most Common) II-Insufficient Quality/Insufficient Quality III-Insufficient Quality (poor formation)/Sufficient Quantity IV-Insufficient Quality/Sufficient Quantity V/VI-Very similar to IV with different histologic features Thus: Type I most mild OI//Type II most severe OI Rest of Types fall between VII/VIII -Very rare -Autosomal Recessive Prognosis Depends on type of OI: Type I - normal lifespan. Type II - death in the first year of life. Type III-wheelchair bound and usually have a shortened life expectancy. Type IV- often need braces or crutches to walk. Life expectancy normal or near normal. Characteristic Symptoms Symptoms Vary According to OI Type: -Bone fractures in childhood/adolescence from Mild trauma -Fractures before birth or little/no trauma -Blue Sclerae -Kyphoscoliosis -Short Stature -Respiratory Problems -Ribcage fragile/deformed-infants have trouble breathing and die almost immediately -Hearing loss -Dentinogenesis Imperfecta Diagnostics Classical: X Rays can reveal fractures and bone deformities to confirm symptoms Novel: Collagen analysis from skin biopsy to check for types/quantities collagen present Gene/DNA analysis to examine characteristic mutant genes DNA sequencing can now find close to 100% of mutations in COL1A1 and COL1A2 genes Treatments Currently No Cure Classical: Essentially Treatment of Manifestations/Symptoms Therapy,Physical Medicine, Orthopedic, Surveillance (children), Dental Novel: Gene Therapy difficult because of many gene variations Bisphosphonates to prevent loss of bone mass (under evaluation) Injection of Human Growth Hormone (under evaluation) Bone Marrow Transplant (under evaluation) History Recognized in Egyptian Mummy from 1000 BC Most Notable Case- Ivan the Boneless, Prince of 9th Century Denmark Carried on shield to battle because unable to walk on “soft legs” Nabil Shaban, actor- documentary: The Strangest Viking 1918 Dr. Van der Hoeve described fragile bones, blue sclera,and deafness as distinct inherited syndrome 1970’s Dr. David Sillence developed “Types” Categorization combining clinical symptoms with genetic components